Peptides and proteins have been widely utilized as pharmaceuticals. It is known to chemically modify pharmaceuticals such as peptides and proteins with polyethylene glycol, dextran, polyamino acids, albumin, inulin, etc. in order to prolong their action in vivo.
On the other hand, attempts have been made to develop targeting preparations of pharmaceuticals such as peptides and proteins. For example, it is reported that the modification of lysozyme and albumin [J. C. Rogers and S. Kornfeld, Biochem. Biophys. Res. Commun., 45, 622 (1971)] and glutaminase [G. Schemer et al., Biochem. Biophys. Acta, 538, 397 (1978)] with asialoglycoproteins is effective for targeting of these substances towards liver. It is also observed that the chemical modification of albumin [L. Fuime et al., FEBS Lett., 146, 42 (1982), L. Fuime et al., Biochem. Pharmacol., 35, 967 (1986)], L-asparaginase [J. W. Marsh et al., J. Biol. Chem., 252, 7678 (1977)] and ribonuclease [G. Wilson, J. Biol. Chem., 253, 2070 (1977)] with lactose enhances the accumulation of these substances at liver. Chemical modification techniques useful in such targeting include the carbodiimide method, the glutaraldehyde method, the SPDP (N-succinimidyl-3-(2-pyridyldithio)propionate) method, the active ester method and the reduction method using sodium cyanoborohydride. The compounds prepared by chemically modifying pharmaceuticals such as peptides and proteins using these techniques are gradually decomposed in vivo to release the pharmaceuticals, but they can not be expected to rapidly release the pharmaceuticals in response to changes in pH or the like.
It is known that the pH of interstitium is lowered to a level of 6.9 in cancer cells etc. and that administration of glucose lowers the pH of interstitium from 6.9 to 6.2 [H. Kahler and W. V. Robertson, J. Natl. Cancer Inst., 3, 495 (1943), P. M. Gullino et al., J. Natl. Cancer Inst., 34, 857 (1965)]. It is also known that inflamed parts have a pH in the acidic range, i.e. pH 6.5 [V. Menkin, Biochemical Mechanism in Inflammation, Thomas, Springfield, III, pp. 69–77 (1956)]. Further, it has been experimentally demonstrated that transient ischemia in rats lowers the pH of the affected part from 7.4 to 6.5 [N. Watanabe et al., Biochem. Pharmacol., 38; 3477 (1989)]. Also known is a pH-sensitive drug delivery system (DDS) for superoxide dismutase (SOD) using a styrene-maleic acid copolymer (SM) [Biochemistry, 28, 6619 (1989), Biochem. Pharmacol., 38, 3477 (1989)]. In this DDS, superoxide dismutase covalently binds to the styrene-maleic acid copolymer (SM-SOD) noncovalently binds to the warfarin site on albumin in blood at pH around neutrality. As the pH is lowered, SM is protonated and the albumin-binding ability thereof is decreased to cause release of SM-SOD.
It is also known that epidermal growth factor (EGF) receptor is excessively expressed at squamous cell carcinoma [S. Ogawa et al., Jpn. J. Cancer Res., 79, 1201 (1988)], and based on this fact, targeting therapy using a carcinostatic agent together with anti-EGF receptor antibody has been attempted [E. A. Pirak et al., Proc. Natl. Acad. Sci. USA, 86, 3778 (1989)]. Tsuchiya et al. have found that by binding EGF to the surface of liposome, the liposome is incorporated into cancer cells via the EGF receptor [S. Tsuchiya et al., Drug Delivery System, 4, 193 (1989)]. However, the EGF receptor is expressed also in normal cells, and it is difficult to specifically target diseased parts.